The purpose of this funding opportunity announcement
(FOA), issued by NINDS, is to invite applications to participate as a
Clinical Site in the Network for Excellence in Neuroscience Clinical Trials.
This clinical research network will develop and conduct multiple, scientifically
sound, possibly biomarker-informed exploratory clinical trials evaluating the
most promising therapies, whether from academic, foundation or industry
discoveries. Examples include Phase 2 clinical trials and clinical research studies
aimed at validating biomarkers and clinical outcomes in preparation for
clinical trials.

The network will provide a robust, standardized, and
accessible infrastructure to facilitate rapid development and implementation
of protocols in neurological disorders affecting adult and/or pediatric
populations.

While the network will not be specific to one disease, it
will have the capacity to coordinate a cadre of specialist investigators to
implement studies efficiently in response to disease-specific opportunities.

It is critical that applicants follow the instructions in
the PHS398
Application Guide except where instructed to do otherwise (in this FOA or
in a Notice from the NIH Guide for Grants and Contracts). Conformance
to all requirements (both in the Application Guide and the FOA) is
required and strictly enforced. While some links are provided, applicants must
read and follow all application instructions in the Application Guide as well
as any program-specific instructions noted in Section IV. When the program-specific
instructions deviate from those in the Application Guide, follow the
program-specific instructions. Applications that do not comply with
these instructions may be delayed or not accepted for review.

The purpose of this funding opportunity announcement (FOA),
issued by NINDS, is to invite applications to participate as a Clinical Site in
the Network for Excellence in Neuroscience Clinical Trials (NEXT). This
clinical research network will develop and conduct multiple, scientifically
sound, possibly biomarker-informed exploratory clinical trials evaluating the
most promising therapies, whether from academic, foundation or industry
discoveries. Examples include Phase 2 clinical trials and clinical research
studies aimed at validating biomarkers and clinical outcomes in preparation for
clinical trials.

The network will provide a robust, standardized, and
accessible infrastructure to facilitate rapid development and implementation of
protocols in neurological disorders affecting adult and/or pediatric
populations. While the network will not be specific to one disease, it will
have the capacity to coordinate a cadre of specialist investigators to implement
studies efficiently in response to disease-specific opportunities.

The network will include multiple Clinical Sites, one
Clinical Coordinating Center (CCC), and one Data Coordinating Center (DCC). The
network is designed to increase the efficiency of clinical trials, to
facilitate patient recruitment and retention, to increase the quality of
neuroscience clinical trials, and to enable public-private partnerships.

BACKGROUND

To translate recent, high quality neuroscience discoveries
into better treatments for people burdened by neurological disorders, efficient
clinical trials are needed. These trials require cooperation and coordination
among investigators, patients and industry partners. Clinical trial networks
can increase the efficiency of research by providing infrastructure,
centralized resources, and access to patients; however, with more than 400
neurological diseases falling under the auspices of NINDS, creating multiple
specialized research networks would not be feasible.

In the traditional model, a consortium of clinical sites is
created for each new multi-center trial. This causes redundancy and delays
because infrastructure is duplicated. Protracted contract negotiations and
approvals at multiple Institutional Review Boards (IRBs) often cause further
delays. In addition, there may be loss of expertise as experienced research
coordinators move to other fields after a trial is completed. The objective of
the network is to increase the efficiency of clinical research through shared
infrastructure for NINDS clinical trials.

RESEARCH
OBJECTIVES

The network aims to share expertise and infrastructure
across diseases, to leverage research resources at clinical sites, and to
flexibly take advantage of clinical research opportunities as they arise in
different disease areas. Finite resources and – especially for rare diseases –
a small pool of potential participants limit the number of large, confirmatory
efficacy (Phase 3) trials that can be conducted at any given time. Therefore,
NINDS aims through the network to support exploratory trials that can provide
more rapid preliminary testing of new treatments.

The objective of the network is to streamline the
implementation of clinical research by using standardized master trial
agreements and infrastructure that utilizes a central IRB of record.

While NINDS has historically funded trials to test drugs
already approved for other indications, the network is designed to assure the
broadest access to any new therapies for patients by carrying out trials coming
from partnerships between NINDS and industry, foundations, or academia. These
trials will be utilizing a variety of the NIH agreement mechanisms (e.g.,
Cooperative Research and Development Agreements [CRADAs]) that maximize industry
participation and support.

It is envisioned that the network will not be
"idle" at any time. During the start-up period, as well as during
periods of time when new network projects will not take up the entire capacity,
the Clinical Site coordinators and Clinical Site principal investigators will
improve the quality and facilitate the implementation of clinical trials at
their sites, by offering their support to ongoing NINDS-funded trials and
enhancing patient recruitment and retention. The CCC will track site
performance as it relates to ongoing NINDS-funded trials.

RESEARCH APPROACHES

Shared Network Infrastructure

This FOA solicits applications for funding of infrastructure
for clinical sites. The additional project-specific funds to support the
implementation of network protocols will be part of future awards. These funds
will be distributed to the Clinical Sites via the CCC on a per-patient basis,
according to protocol budgets approved by the network Steering Committee (SC)
and via master trial agreements with the Clinical Sites. The Clinical Sites
must be willing to follow this funding arrangement for each protocol they
choose to participate in.

The network will give preference to clinical sites agreeing
to use a central IRB of record, to accelerate IRB approval in multi-center
trials. To that effect, the network will use a “federated" IRB model.
This model gives participating institutions the option to choose one of three
tiers of IRB review:

Tier 1 indicates the reliance on a central IRB as IRB of record;

Tier 2 indicates an option to designate a central IRB as IRB of
record in addition to a local IRB;

Tier 3 indicates the reliance on local review.

Applicants and their institutions should indicate their
willingness to participate in a federated IRB model with the option to
designate one central IRB as IRB of record, as an efficient alternative to the
currently prevalent local review of the initial protocol and progress reports
and adverse events. The CCC will have to coordinate a central IRB of record and
manage all required IRB communication and documentation including but not
limited to tracking approval, maintaining regulatory documents, communicating
with the local IRBs, and handling adverse event reporting and notifications.

Clinical Sites will be offered network-approved
fee-for-service reimbursement for the per-patient cost from the CCC to
implement protocols, according to budgets approved by the SC and NINDS for each
protocol. Sites will have the option not to participate, but will not be able
to negotiate the direct costs as funded by NINDS for a given trial, and as
approved by the network SC.

Network Projects

Over the 7-year project period, the network will conduct
approximately 5-7 clinical research projects, and will promote the
implementation of ongoing NINDS-funded clinical trials. The exact number of
protocols supported in the 7-year program will depend on the nature and extent
of the investigations proposed and the availability of funds.

This RFA is soliciting applications from centers that have
access to patient populations with a variety of neurological disorders.

To ensure that the network is efficiently using resources
from its inception, a short-term clinical research project will begin soon after
the network has been established. It is anticipated that this first project
will be a biomarker validation study for spinal muscular atrophy (SMA). A separate
future FOA will solicit applications for this SMA protocol. Additional trials
will be selected from project proposals from industry and academic
investigators submitted in response to a second, future FOA that will solicit
applications for Phase 2 clinical trials to be implemented through the network.
It is anticipated that at least one of the total trials conducted will be
targeted to children.

Following a second level of review by the NINDS advisory
council, NINDS will select protocols to be fully developed by a protocol lead
team consisting of the Project Director/Principal Investigator (PD/PI),
disease-experts as co-investigators, and the network representatives.

The final protocol will be approved after technical review
by a Protocol Review Committee. A subset or all of the Clinical Sites will
then be invited to participate in a given project and will have the option to
accept or decline, depending on their capacity, interest, and patient
population relevant to the specific protocol. It is also possible that non-network
sites may be added ad-hoc for a specific project, for their expertise and
patient population to complement the network sites.

RESEARCH
TOPICS

Each Clinical Site's Scope of Work includes, but is not
limited to:

Identifying an experienced clinical trials expert with a track
record in successfully conducting clinical research as a PD/PI.

Reaching out to the local medical community and to potential
referring physicians and identifying potential co-investigators with
disease-specific clinical research expertise interested in working with the PD/PI.
The investigators may be from either the same institution or different
affiliated institutions.

Identifying an experienced coordinator to work full-time with the
investigators on network projects, and participate in network-wide
communications, training, protocol review, and patient recruitment and
retention. The coordinator’s primary responsibilities will be to the network
trials. However, the coordinator will also be expected to assist with other
NINDS-funded clinical trials at their site when network activities are not
demanding their full-time effort and thus, the network will not
"idle" at any time.

Participating in a minimum of four network clinical research
projects or trials during the funding period. A Clinical Site PD/PI and any of
the potential disease expert co-investigators may submit trial applications for
peer-review in response of the future network Phase 2 PAR, and if successful may
assume responsibility for being the lead Clinical Site on a given
peer-reviewed, network-approved research project, which would entail providing continued
leadership in protocol development and implementation in collaboration with the
network.

Implementing shared protocols involving, but not limited to: 1)
assembling a local research team, 2) establishing contractual agreements, 3)
obtaining IRB approval & informed consent, 4) recruiting, treating, and
following patients according to the study protocols, and 5) collecting and
entering accurate, high quality data into the central web-based data management
system. To increase the efficiency and reduce start-up time, sites are
required to work through standardized master trial agreements agreed to by the network.

Accurately identifying and recruiting all eligible subjects for network-
and other NINDS-supported clinical research projects, and retaining participants
throughout the follow-up period as required by protocol. Reaching out to
patients for potential trial participation. Ensuring human subjects'
protections and adequate gender and minority representation among subjects
enrolled at network Clinical Sites, and ensuring protocol adherence.

Tracking and reporting trial and performance data to the CCC and/or
NINDS on a regular and frequent basis, including recruitment, retention, and
adverse events, as required per protocol and by the IRB and regulatory bodies.

Working with the DCC to ensure complete, accurate, and timely
data entry, as well as rapid and complete resolution of any data queries, and
to maintain a high level of data quality and completeness. Clinical Site PDs/PIs
are also expected to cooperate with monitoring visits and to assist the DCC
with the development and implementation of: 1) common data elements, 2) data
entry forms, and 3) public dissemination of project results, as needed.

Helping new clinical investigators develop skills and experience
to progress to more senior or experienced status, when appropriate.

Participating in all network Steering Committee (SC) meetings and
maintaining cooperative interactions with all other Clinical Sites, the CCC,
and the DCC in all aspects of the network.

Assisting the network SC by serving on SC working groups
developed on an as-needed basis, and charged with the planning and
implementation of protocols, as well as with recommendations on issues such as
publications guidelines, quality control, etc.

Leveraging local research resources. Applications from
institutions that have a General Clinical Research Center (GCRC) or Clinical
and Translational Science Award (CTSA) funded by the NIH National Center for
Research Resources should identify the resources that could be available to
support the proposed network Clinical Site, commenting particularly on those
aspects that will enhance their programmatic and scientific efficiency. In
such a case, a description of the GCRC or CTSA and how the applicant proposes
interacting with it should be included, as well as letter of agreement from
either the GCRC/CTSA Program Director or PI. Having a GCRC or CTSA at the
institution is not a requirement for application.

Network Structure and Management

The NINDS Network of Excellence in Neuroscience Trials will
include: one Data Coordinating Center (DCC), one Clinical Coordinating Center
(CCC), and up to 25 Clinical Sites. A network Clinical Site should be able to
conduct trials in adult populations, pediatric populations, or both. Special
consideration will be given to children's hospitals. Investigators at the NIH
Clinical Center may also function as an additional clinical site.

The NINDS will be responsible for organizing and providing
overall support for the network. The NINDS Office of Clinical Research staff
and the NINDS Office of Grants Management will be responsible for the overall
management of the network. In addition to regular grant stewardship, an NINDS
Project Scientist will be involved substantially with the awardees as a NINDS
partner, consistent with the Cooperative Agreement mechanism. The NINDS will
appoint the Data and Safety Monitoring Board (DSMB) and the Scientific Advisory
Board (SAB).

A Steering Committee (SC) composed of three principal
investigators representing the Clinical Sites, the DCC PD/PI, the CCC PD/PI,
the PDs/PIs of active network projects, and the NINDS Project Scientist will be
the main governing body of the network. The NINDS will appoint an SC Chair who
may or may not be independent of the Clinical Sites, the CCC and the DCC, to
preside over SC meetings and serve as the SC representative to the SAB. The
SAB is an external group of experts who will review the network program and
advise the network investigators and the NINDS.

All major scientific decisions will be determined by majority
vote of the SC;

Each SC member will have one vote; the SC Chair will cast a vote
in case of a tie;

The protocol lead PDs/PIs of approved network protocols will
become SC members for the duration of the project they are leading;

The initial three Clinical Site representatives will be appointed
by NINDS to the SC for a 2 to 3-year term;

The second slate of SC investigator-members will consist of the
highest overall enrolling investigator and two investigators elected by their
peer investigators to a 2-year term. For continuity, one of the three initial
SC investigator members will serve on the committee for 2 years, and two will serve
for 3 years so that not all tenures expire at the same time;

It is anticipated that the SC will meet two times per month by
telephone conference call and at least three times per year by in-person
meetings;

The SC will have primary responsibility for network governance.
SC working groups will be established by the SC to perform specific functions,
such as, for example:

Protocol planning and development;

Publications;

Per-patient budget approval;

Quality control assurance;

Conflict of interest.

Awardees will be required to accept and implement policies including
standardized master trial agreements approved by the SC.

The Data Coordinating Center (DCC) will support protocol data
management, data quality control (including data monitoring), and statistical
design and analysis. The DCC will also initiate and coordinate activities to
promote standardization of data elements using the NINDS common data elements
when available, or help develop common data elements and standardized
protocols. See RFA-NS-11-010 for more details describing the responsibilities of the network DCC.

The Clinical Coordinating Center (CCC) provides overall study
coordination, working closely with the DCC and the Clinical Sites. The CCC
will coordinate the activities of the SC, develop and implement investigator
and staff training programs and meetings, oversee drug acquisition and
distribution as needed, work closely with the project-specific lead protocol teams,
support project investigators in IND submission and reporting to the Food and
Drug Administration (FDA), establish and maintain standardized master trial agreements
with the network sites and distribute funding for network trial projects,
maintain regulatory documents and coordinate the central IRB process, support
outreach to patients and inclusion of patients in protocol and recruitment plan
development, editorial and meeting coordination for manuscript preparation, and
development of operational and publication guidelines within the framework
outlined by the network CCC RFA. See RFA-NS-11-009 for more details describing the responsibilities of the network CCC.

An independent DSMB, established by the NINDS in accordance with
NIH policies and with input from the SC, will monitor patient safety, and
review study performance.

Section II. Award Information

Funding Instrument

This FOA will use the NIH Cooperative Agreement award
mechanism (U10). In the cooperative agreement mechanism, the PD(s)/PI(s)
retain(s) the primary responsibility and dominant role for planning,
directing, and executing the proposed project, with NIH staff being
substantially involved as a partner with the PD(s)/PI(s), as described under
the Section VI.2.
Administrative Requirements, "Cooperative Agreement Terms
and Conditions of Award".

Application Types Allowed

New

The OER
Glossary and the PHS398 Application Guide provide details on these application
types.

Funds Available and Anticipated Number of Awards

The total amount of funding that NINDS expects to award
through this announcement is up to $52.5 Million.

The anticipated number of awards is up to 25.

Although the financial plans of the IC provide support for
this program, awards pursuant to this funding opportunity are contingent upon
the availability of funds.

Award Budget

The expected direct cost amount for individual awards is
up to $200,000 annually for 7 years.

Facilities and Administrative (F&A) costs requested by
consortium participants are not included in the direct cost limitation. See NOT-OD-05-004.

NIH grants policies as described in the NIH Grants Policy
Statement will apply to the applications submitted and awards made in
response to this FOA.

Award Project Period

This is a one-time solicitation to fund the network for 7
years. Plans beyond the current funding period are undetermined.

NIH grants policies as
described in the NIH Grants
Policy Statement will apply to the
applications submitted and awards made in response to this FOA.

Section
III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions:

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Non-domestic (non-U.S.) Entities (Foreign Organizations) are
not eligible to apply. Foreign (non-U.S.) components of U.S. Organizations are not allowed.

Required Registrations

Applicant organizations must complete the following registrations
as described in the PHS398 Application Guide to be eligible to apply for or
receive an award. Applicants must have a valid Dun and Bradstreet Universal
Numbering System (DUNS) number in order to begin each of the following
registrations.

All Program Directors/Principal Investigators (PD/PIs) must
also work with their institutional officials to register with the eRA Commons
or ensure their existing eRA Commons account is affiliated with the eRA Commons
account of the applicant organization.

All registrations must be completed by the application due
date. Applicant organizations are strongly encouraged to start the registration
process at least four (4) weeks prior to the application due date.

Eligible Individuals (Project Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Project Director/Principal
Investigator (PD/PI) is invited to work with his/her organization to develop an
application for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for NIH support.

The Principal Investigator for a Clinical Site will be a
clinical trials expert with a track record in successfully implementing
clinical trials.

Institutions will be required to document commitment to the PD/PI
by providing departmental and institutional support letters, and are encouraged
to demonstrate support via other means (e.g., additional protected time,
departmental research leadership position, facilities, space, or resources for
the PD/PI and/or Clinical Site).

Applicants are strongly encouraged to list, in addition to the PD/PI,
several co-investigators with disease-specific clinical research expertise and
access to a clinic population who are interested in working with the PD/PI. At
an institution with pediatric and adult patients, the disciplines appropriate
for clinical site investigators and co-investigators include pediatric and
adult neurologists, neurosurgeons, neuropsychologists, neuroradiologists or
other related specialists with a strong interest in clinical research and a
wide range of disease interests such as behavioral neurology, neuromuscular
disorders, movement disorders, vascular neurology, neuroimmunology, or general
neurology. These experts may be from the same institution or different
institutions.

Only one Clinical Site application per institution (normally
identified by having a unique DUNS number or NIH IPF number) is allowed.

Awards for a CCC and a Clinical Site may be made to the same
institution. However, it is preferable that the CCC and the Clinical Site grant
at a given institution be awarded to two investigators, to ensure that the CCC
activities as well as the local Clinical Site activities receive full attention.

NIH will not accept any application in response to this FOA
that is essentially the same as one currently pending initial peer review
unless the applicant withdraws the pending application. NIH will not accept any
application that is essentially the same as one already reviewed. Resubmission applications are not permitted in response to this FOA.

Renewal applications are not permitted in
response to this FOA.

Section IV. Application and
Submission Information

1. Address to Request Application Package

Applicants are required to prepare applications according to
the current PHS 398 application forms in accordance with the PHS 398
Application Guide.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the PHS398
Application Guide, except where instructed in this funding opportunity
announcement to do otherwise. Conformance to the requirements in the
Application Guide is required and strictly enforced. Applications that are out
of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

Pre-Application Meeting: The NINDS anticipates holding a technical
assistance meeting in January 2011 (now December 17, 2010 per NOT-NS-11-005), through a teleconference to which all
interested prospective applicants are invited. Program and review staff will
make presentations that explain their goals and objectives for the NEXT
Initiative and answer questions from the attendees. Prospective applicants are
urged to monitor the NIH Guide for Grants and Contracts regarding a Notice for
the date and time of the meeting (http://grants.nih.gov/grants/guide/index.html).

Application Submission

Applications must be prepared using the PHS 398 research
grant application forms and instructions for preparing a research grant
application. Submit a signed, typewritten original of the application,
including the checklist, and three signed photocopies in one package to:

All page limitations described in the PHS398 Application
Guide must be followed, with the following exceptions or additional
requirements:

Research Strategy section is limited to 30 pages. Applications
received that exceed these page limitations will not be reviewed.

Research Plan

All instructions in the PHS398 Application Guide must be
followed, with the following additional instructions:

Applications should include the following information
in the relevant subsections:

1)
Leadership Plan

The PD/PI should describe, in the Approach section of
the Research Strategy, how clinical trials and research at the Clinical Site will
be strategically supported by the network Clinical Site PD/PI and coordinator.

2)
Collaboration Plan

In the relevant sections of the Biosketch, Resources/Facilities,
the Research Strategy or, where applicable, in the Multiple PD/PI Leadership Plan,
applicants should state their general support of collaborative research and
their willingness to participate in a collaborative and interactive manner with
other Clinical Sites, the Data Coordinating Center, and the NINDS and its
partners in all aspects of the network program. Applicants are encouraged to
describe any special expertise or unique strengths they can offer to the
collaborative effort (e.g., team leadership and training, protocol adherence
strategies, dissemination activities, recruitment strategies). Applicants
should describe the potential pool of co-investigators at the site and their
area of expertise. The applicant should indicate how co-investigators will be
identified, motivated, and integrated into the network, and how the network
team will support the co-investigators. A detailed plan must be included in
the Research Strategy section of the application on outreach and collaboration
with other clinical investigators at the Clinical Site, because the success of the
network at the Clinical Site will depend on collaboration with co-investigators
with disease-specific clinical research expertise and a clinic population who
are interested in working with the PD/PI.

In the Budget Justification section, applicants
should indicate their willingness to attend all network investigator meetings,
which will include conference calls at least two times a month and in-person
meetings at least three times a year.

In the Approach section of the Research Strategy, applicants
should discuss their willingness, and that of the institutions involved, to
establish standardized master trial agreements with the Clinical Coordinating
Center to reduce trial start-up time. Agreeing on master trial agreement
templates for recurring issues (e.g., publications) will expedite trials
initiated under these standardized master trial agreements.

In the Resources/Facilities section, applicants should
discuss their capability to participate in a distributed data entry system,
since Clinical Sites should be able to interact with the Data Coordinating Center
to transmit and edit data.

3)
Recruitment and Outreach Plan

This section should be briefly summarized in the 30
page Research Strategy, and additional detail including a table (see below)
should be provided either in the Research Strategy or in the Human Subjects
section of the application. Applicants should demonstrate (with reference to
specific, objective sources of data on the size of the available population)
access to a sufficient number of patients to participate in a wide range of
neuroscience clinical trials. This is best demonstrated by showing a table
that lists by disease the potential co-investigators and their qualifications,
track record and interest, as well as the patient population, e.g., total
number of patients with the disease seen annually, number of patients currently
participating in trials, number of new patients per year for the last full
calendar year. SMA should be specifically included among the diseases listed,
but a site does not have to have access to SMA patients to be eligible to apply.
The applicant should also indicate how outreach into the community, to
referring physicians and to patients will take place, what actions and
materials will be used to support recruitment of patients, and how patients
will be included in the conception, planning and implementation of trials so
that a strong partnership between investigators and patients can serve as a foundation
for successful trial recruitment and retention.

Patient access may be accomplished by establishing
links with other groups (e.g., other health care providers in the community,
such as neurology practices, primary care practitioners, pediatricians, local
hospitals, rehabilitation centers, patient support groups, and health
maintenance organizations) in addition to the applicant’s institution. If
links with other groups are anticipated, the application should include a plan in
the Approach section of the Research Strategy with appropriate letters of support
(appended in the Letters of Support section of the application) describing (1)
how the applicant Clinical Site will link to and operate with the other groups,
and (2) how the Clinical Site will monitor the quality of the other group’s
performance (screening, and, if applicable, patient recruitment and data
collection).

The application should include a brief description of
anticipated problems with recruitment and plans for addressing these problems.
Note that proposed solutions to recruitment problems may not include requesting
additional funds under this FOA.

4)
Leveraging Local Clinical Research Resources Plan

The applicant should describe in the Resources/Facilities
section how local clinical research resources such as equipment, space and
research staff will relate to the network, and, if applicable, how the network
will integrate CTSA resources.

5)
Plan to Increase the Efficiency of the Clinical Research Enterprise at the Clinical
Site

For new trials, plans to reduce start up time by
increasing the efficiency of contracting and IRB review through use of standardized
master trial agreements and federated IRB models and, for ongoing NINDS funded
trials (whether network trials or other), means to monitor and track
performance and to increase recruitment and retention should also be described
in the Research Strategy.

6)
Performance Monitoring and Potential Interventions Plan

In the Research Strategy section, the application
should include a plan for how the PD/PI will monitor performance and collect
data on start up, recruitment and retention for new and potentially also for
ongoing NINDS-funded clinical trials at the Clinical Site.

7)
Training Plan

The network presents a rich environment for young
investigators to be exposed to and develop additional research skills and to
assist them in progressing to more senior status. The applicant should describe
in the Approach section of the Research Strategy, the plans to reach out to
young investigators.

In
addition, the application should include the following:

A table listing potential co-investigators at the Clinical Site,
along with their disease-specific clinical research expertise and the
approximate number of patients they see in their clinic population, by disease
of interest. While key personnel should be separately listed in the
application, the above table should be included in the Research Strategy
section.

A table listing the current and the five most recent
multi-center trials that the site has participated in should be included in the
“Preliminary Data” section of the Research Strategy, consisting of the
following:

The complete name of the trial;

The funding source;

The name of the site PD/PI;

The start-up time from award to IRB approval;

The time from initiation of contract negotiation with lead site
to contract executed;

The time from award to first patient screened;

The time from award to first patient enrolled;

The enrollment rate;

The total number of patients enrolled at the site;

The proportion of patients lost to follow-up;

The number of protocol violations at the site.

Letters of support from potential co-investigators at the
Clinical Site, affirming an interest in collaborating with the potential local
network site PD/PI and with the network as such, describing their expertise,
track record, interest, and access to patient populations. These should be
included in the separate Letters of Support section of the application.

An institutional letter of support from the applicant's
departmental and/or institutional leadership should be included in the Letters
of Support section of the application.

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS) as provided in the PHS398
Application Guide.

It is expected that the network research resources
such as Manual of Operations, study manuals, case-report forms, phenotype
ascertainment instruments, and newly developed common data elements will be
made available to the public after publication of study findings (e.g., through
NINDS Common Data Elements [CDEs], see http://www.commondataelements.ninds.nih.gov/,
or the National Technical Information Service, see http://www.ntis.gov/index.aspx).

Appendix

Do not use the appendix to circumvent page limits. Follow
all instructions for the Appendix (please note all format requirements) as
described in the PHS398 Application Guide.

Applications must be received on or before the due dates in Part I. Overview Information. If an application is received after that date, it will not
be reviewed

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Qualifications and Experience

Applicants should describe qualifications and experience in
the Biosketches and in the appropriate narrative sections of the application (Background/Preliminary
Data section of the Research Strategy). It is anticipated that participation
in the network will be a complex and time-consuming undertaking and applicants
for Clinical Sites must have the necessary experience and expertise to oversee
or support clinical trials in pediatric and/or adult patients with neurological
disorders.

Links with NIH Resource Centers

Applications from institutions that have a General Clinical
research Center (GCRC) or Clinical and Translational Science Award (CTSA)
funded by the NIH National Center for Research Resources should identify the
resources that could be available to support the proposed network Clinical
Site, commenting particularly on those aspects that will enhance their
programmatic and scientific efficiency. In such a case, a description of the
GCRC or CTSA and how the applicant proposes interacting with it should be
included in the Resources/Facilities section, as well as letter of agreement from
either the GCRC/CTSA Program Director or PI in the Letters of Support section
of the application. Having a GCRC or CTSA at the institution is not a
requirement for application.

Budget

A detailed budget for the
Clinical Sites should be presented.

The budget does not need to
include Data Coordinating Center or Clinical Coordinating Center costs nor
costs for training, investigator meetings, or patient enrollment, treatment or
follow-up.

Clinical Site applicants
should consider the following issues regarding Clinical Site core budgets. It
is expected that the individual Clinical Site will require a minimum level of
effort to sustain the organizational aspects of the network. This includes an
expected minimum of 2.4 - 3 person months total effort for the leadership (PD/PI);
a full-time professional clinical research coordinator over the course of the
project period (keeping in mind that protocol funds will include time for study
personnel on a per-patient/service basis required to execute protocols over and
above personnel proposed in the Clinical Site core budget); and travel costs
for approximately three trips each year for two team members to attend SC
meetings in Bethesda, MD, and other travel or meetings related to network
operations.

The total should not exceed
$200,000 direct costs per year in years 1-7 (all of which will be 12-month
project years). The release of funds will be milestone-driven, according to
milestones to be specified in the Notice of Award. Clinical Sites who will not
meet the milestones would be replaced, if necessary. Facilities and
administrative costs requested by consortium participants are not included in
the direct cost limitation (see NOT-OD-05-004). All costs in the proposed
budget should include appropriate justification.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review
Information

1. Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a
sustained, powerful influence on the research field(s) involved, in consideration
of the following review criteria and additional review criteria (as applicable
for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

How will the proposed clinical site contribute to the advancement
of clinical research and clinical trials within the framework of the network?

Investigator(s)

Are the PD/PIs, collaborators, and other researchers
well suited to the project? If Early Stage Investigators or New Investigators,
or in the early stages of independent careers, do they have appropriate
experience and training? If established, have they demonstrated an ongoing
record of accomplishments that have advanced their field(s)? If the project is
collaborative or multi-PD/PI, do the investigators have complementary and
integrated expertise; are their leadership approach, governance and
organizational structure appropriate for the project?

Does the PD/PI have a track record of working collaboratively?

Does the PD/PI have a track record in successfully implementing
clinical trials?

Is there evidence of experience in and willingness to participate
appropriately in a collaborative program as described in this RFA?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned
and appropriate to accomplish the specific aims of the project? Are potential
problems, alternative strategies, and benchmarks for success presented? If the
project is in the early stages of development, will the strategy establish
feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Are interactions/communications between investigators at the site
and the community (e.g., referring physicians and patient populations) clearly
described and creatively optimized?

Does the investigator have adequate plans to recruit patients
with a variety of neurological disorders and with diverse gender/minority
representation, as well as plans for human subjects' protection, good clinical
practices (GCP)?

Is the investigator willing and likely sufficiently available to
participate in network-wide meetings, teleconferences, and SC working groups?

Is the timeline for IRB approvals and contract negotiations
sufficient?

Is the institution able to utilize a central IRB of record that can
accept standard network standardized master trial agreements for per-patient
cost of clinical programs?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Is there adequate evidence of institutional and departmental
commitment to the PD/PI (e.g., additional protected time, departmental research
leadership position, facilities, space, or resources for the PD/PI and/or CS)?

Based on data provided from the current and five most recently
completed clinical trials at the site:

What is the institution's track record with regards to trial
start-up time?

What is the institution's track record with regards to IRB review
time?

What is the institution's track record with regards to contract
negotiation?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations - Overall

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by the NINDS Scientific Review Branch (assignments will be shown in the eRA Commons), in
accordance with NIH peer
review policy and procedures, using the stated review
criteria.

As part of the scientific peer review, all applications will:

Undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall
impact/priority score.

Receive a written critique.

Applications will be assigned on the basis of established
PHS referral guidelines to the appropriate NIH Institute or Center and will
compete for available funds with all other recommended applications submitted in response to this FOA . Following initial peer review, recommended applications
will receive a second level of review by the National Advisory Neurological Disorders and Stroke Council.

The following will be considered in making funding
decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review;

Availability of funds;

Relevance of the proposed project to program priorities;

Clinical trial expertise, track record, and resources;

Track record and willingness to collaborate with other clinical
researchers at the applicant’s institution, breadth of expertise among
potential co-investigators;

Willingness, and evidence of potential, to participate in all
aspects of the network program, including protocol development and other SC
working groups, and participation in teleconferences and in person meetings;

Willingness to work collaboratively and strong track record of
successful collaboration and participation in large, multi-center research
teams;

Recent and current NINDS-funded projects in the clinical
neurosciences at the applicant’s institution;

Ability to begin operations immediately;Agreement to accept the
Cooperative Agreement Terms and Conditions of Award delineated in this FOA (see
Section VI.2.A);

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the
cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic
involvement with the awardees is anticipated during the performance of the
activities. Under the cooperative agreement, the NIH purpose is to support and
stimulate the recipients' activities by involvement in and otherwise working
jointly with the award recipients in a partnership role; it is not to assume direction,
prime responsibility, or a dominant role in the activities. Consistent with
this concept, the dominant role and prime responsibility resides with the
awardees for the project as a whole, although specific tasks and activities may
be shared among the awardees and the NIH as defined below.

The
PD(s)/PI(s) will have the primary responsibility for:

Trial
participant safety, implementation of network protocols in accordance with GCP
and other regulatory requirements, participant recruitment and retention,
reporting to the NINDS, CCC, DCC, and DSMB.

Awardees will retain custody of and have
primary rights to the data and software developed under these awards, subject
to Government rights of access consistent with current DHHS, PHS, and NIH
policies.

NIH
staff have substantial programmatic involvement that is above and beyond the
normal stewardship role in awards, as described below:

The NINDS staff working with the network investigators will
develop performance milestones for clinical sites. Failure to meet the agreed
upon milestones may result in reduced funding or early termination of the
cooperative agreement.

An NINDS Project Scientist will have substantial programmatic
involvement that is above and beyond the normal stewardship role in awards, as
described below.

An agency program official
or IC program director will be responsible for the normal scientific and
programmatic stewardship of the award and will be named in the award notice.

Areas
of Joint Responsibility include:

A SC composed of three Clinical Site principal investigators
representing the Clinical Sites, the Data Coordinating Center principal
investigator, the Clinical Coordinating Center principal investigator, the PDs/PIs
of active network projects, and the NINDS Project Scientist will be the main
governing body of the network. The NINDS will appoint a SC Chair who may or
may not be independent of the Clinical Sites, the CCC and the DCC to preside
over SC meetings and serve as the SC representative.

The Clinical Site PD/PI and coordinator are expected to
participate in all network teleconferences and investigator meetings. They are
also expected to assist the network SC in deciding how peer-reviewed research
and trial proposals will be selected and prioritized for implementation through
the network.

Clinical Site PDs/PIs will also be expected to serve on SC
working groups established on an as-needed basis and charged with tasks such as
the planning and development of protocols, publication guidelines, quality assurance
monitoring, etc.

Dispute
Resolution:

Any disagreements that may arise in scientific or
programmatic matters (within the scope of the award) between award recipients
and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel
composed of three members will be convened. It will have three members: a
designee of the Steering Committee chosen without NIH staff voting, one NIH
designee, and a third designee with expertise in the relevant area who is
chosen by the other two; in the case of individual disagreement, the first
member may be chosen by the individual awardee. This special dispute resolution
procedure does not alter the awardee's right to appeal an adverse action that
is otherwise appealable in accordance with PHS regulation 42 CFR Part 50,
Subpart D and DHHS regulation 45 CFR Part 16.

A final progress report, invention
statement, and Financial Status Report are required when an award is
relinquished when a recipient changes institutions or when an award is
terminated.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.FSRS.gov on all subawards over $25,000. See
the NIH Grants Policy Statement for additional information on this reporting
requirement.

Section VII.
Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.